The American Cancer Society estimates over one million new patients were diagnosed with skin cancer in 2005, representing 40% of all invasive and in situ cancers that occurred in the United States that year. The magnitude of these statistics suggests that the treatment of skin cancer in the United States is a significant problem for patients as well as our healthcare system. Conclusive evidence has demonstrated that the main environmental risk factor for developing skin cancer is exposure to ultraviolet wavelengths of light (UVB) found in sunlight. Although skin cancer can occur at any age, there is a strong correlation between the development of skin cancer and advancing age. In fact, the majority of skin cancers are found in people over the age of 60;therefore, age is a second risk factor for the development of skin cancer. While the correlation between aged epidermis and skin cancer is obvious, the mechanism responsible for this relationship remains obscure. Recent in vitro evidence as well as epidemiological data suggests one possible mechanism may involve alterations in the insulin-like growth factor-1 receptor (IGF-1R) signaling network. Using normal human keratinocytes grown in vitro, activated IGF-1Rs protect keratinocytes from UVB-induced apoptosis;however, while UVB-irradiated keratinocytes with activated IGF-1Rs survive, they are incapable of further cellular replication, in fact they are senescent. However, the critically important observation was that in the absence of IGF-1R activation, keratinocytes are more sensitive to UVB-induced apoptosis, but the keratinocytes that do survive retain the capacity to proliferate. In the skin, keratinocytes express the IGF-1R but they do not synthesize IGF-1. Dermal fibroblasts support the proliferation of keratinocytes in the epidermis by secreting IGF-1. Interestingly, as dermal fibroblasts age (or senesce), their capacity to produce IGF-1 is severely diminished;therefore, in aged skin keratinocytes are provided with a reduced supply of IGF-1. The hypothesis to be tested in this proposal is that the reduced activation of the IGF-1R due to deficient fibroblast function could be an important factor in the dramatic increase of non-melanoma skin cancer observed in geriatric individuals. Through the use of in vitro three-dimensional skin organ cultures, we will determine the importance of proper fibroblast function on the sensitivity of keratinocytes to UVB irradiation. These studies will provide important insights into the mechanism(s) by which UVB (and other genotoxic insults) can result in carcinogenesis, and thus provide impetus for novel pharmacological strategies not only for keratinocytes but potentially other epithelial-derived cancers. PUBLIC HEALTH RELEVANCE: The experiments described in this proposal are designed to further expand our understanding of the roles of IGF-1 and the IGF-1R following UV irradiation in an intact skin model system. The information derived from these studies will better enable us to design experiments defining UV irradiation and cutaneous carcinogenesis in vivo and potentially create therapeutic therapies to prevent the initiation of non-melanoma skin cancer.